Novel Treatment of menopausal hot flushes with an extradiol prodrug

描述(由申请者提供)：潮热在世界范围内构成了一个重大的公共卫生问题。这些围绝经期症状是女性在更年期过渡期间寻求医疗服务的主要原因。潮热经常对女性的生活质量产生负面影响，因为它们与导致疲劳、抑郁、易怒和健忘的睡眠障碍有关，以及严重的身体不适和对工作的负面影响。目前的治疗方法包括雌激素或激素(雌激素、孕激素)疗法(ERT和HRT)、可乐定、选择性5-羟色胺和/或去甲肾上腺素再摄取抑制剂，以及加巴喷丁。虽然ERT或HRT在预防潮热方面是有效的，但大量女性不能或不想服用雌激素。其他疗法的疗效值得怀疑。因此，对更好、更安全的ERT或HRT存在巨大的未得到满足的需求。在这一应用中，我们建议17b-雌二醇的对苯二酚(Q-E1)有可能被认为是最佳的ERT。我们早些时候已经证明，雌酮的对苯二酚(Q-E1)具有前药物的功能，在其吸收后，其在选择性组织中通过涉及NADP(H)的酶催化机制被转化为E1。这种转换在大脑中有效，但在子宫、乳房或脑下垂体中无效。因此，雌激素的喹酚治疗不像任何其他雌激素，包括经常使用的倍美力，不具有促子宫(斑点、出血、癌症)和促乳房(乳腺癌)的倾向。由于雌二醇是人类卵巢产生的最主要也是最有效的雌激素，我们建议将Q-雌二醇作为治疗围绝经期症状的前体药物，主要是潮热。我们的试验数据强烈表明，Q-E2可以阻止潮热大鼠模型中的潮热症状，但在阻止潮热症状的剂量下，并不会刺激MCF-7乳腺细胞或子宫的增殖。因此，Q-E2似乎是一种新的、安全的、最佳的缓解围绝经期潮热的ERT。该建议描述了一系列研究，旨在(1)剖析Q-E2/E2在参与体温调节的大脑区域的转化动力学；(2)利用两种大鼠潮热模型确定其皮下和口服Q-E2的最佳剂量；(3)提供证据表明Q-E2的有益作用是通过雌激素受体介导的；以及(4)证实Q-E2在子宫和乳腺中缺乏作用，以及Q-E2长期给药对去卵巢大鼠骨骼的有益影响。一种新颖而安全的ERT的发现将改善全世界数亿围绝经期妇女的生活质量，因此将对公共卫生产生巨大影响。尽管还没有进行实验测试，Q-E2也可能是男性男性更年期治疗的选择。此外，我们在这里提出的亲药物方法可能会为其他相关或非相关疗法的药物发现提供动力。公共卫生相关性：围绝经期潮热在世界范围内构成一个重大的公共卫生问题。虽然激素替代疗法缓解了大多数女性的潮热，但大量围绝经期女性不能或不想服用激素。因此，对更年期症状更好、更安全的治疗仍有巨大的需求未得到满足。该提案通过研究一种潜在的无责任雌激素替代疗法来解决这一未得到满足的需求，即使用雌激素的对苯二酚作为前药方法。这种前药在大脑中转化为雌激素，但不会在子宫和乳房中转化为雌激素，因此，它可以在热潮红的动物模型中钝化潮热。

DESCRIPTION (provided by applicant): Hot flushes pose a significant public health concern world-wide. These perimenopausal symptoms are the primary reason that women seek medical care during the menopausal transition. Hot flushes often negatively impact the quality of life of women because they are associated with sleep disturbances resulting in fatigue, depression, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work. Current therapies include estrogen or hormone (estrogens + progestins) therapies (ERT and HRT), clonidine, the selective serotonin and/or norepinephrine reuptake inhibitors, and gabapentine. Although ERT or HRT is efficacious in preventing hot flushes, a large number of women cannot or do not want to take estrogen. The efficacy of the other therapies is questionable. Therefore, there is a huge unmet need for a better and safer ERT or HRT. We propose in this application that para-quinol of 17b-estradiol (Q-E1) has the potential to be considered as the optimal ERT. We have shown earlier that para-quinol of estrone (Q-E1) functions as a pro-drug and following its absorption its is converted in selective tissues to E1 via an enzyme catalyzed mechanism involving NADP(H). This conversion is effective in the brain but not in the uterus, breast, or the pituitary gland. Therefore, treatment with quinols of estrogens do not have uterotropic (spotting, bleeding, cancer) and mammotropic (breast cancer) liabilities like any other estrogens, including the frequently used Premarin. Since E2 is the primary and most potent estrogen produced by the human ovary, we propose to consider Q-E2 as a pro-drug for the treatment of perimenopausal symptoms, primarily hot flushes. Our pilot data strongly indicate that Q-E2 blocks hot flush symptoms in a rat model of hot flush, but does not stimulate proliferation in MCF-7 breast cells or the uterus at doses that block the hot flush symptoms. Therefore, Q-E2 seems to be a novel, safe, and optimal ERT for alleviating perimenopausal hot flushes. The proposal describes a series of studies aimed at (i) dissecting out the dynamics of Q-E2/E2 conversion in brain areas involved in thermoregulation, (ii) establishing the optimal dose of Q-E2 following its subcutaneous and oral administration using two rat models of hot flush, (iii) provide evidence that the beneficial actions of Q-E2 are mediated via estrogen receptors, and (iv) confirm the lack of action in the uterus and breast, and the beneficial effects in the bone following its chronic administration to ovariectomized rats. The discovery of a novel and safe ERT would improve the quality of life of hundreds of millions of perimenopausal women world-wide and thus, would have a tremendous impact on public health. Although has not been tested experimentally, Q-E2 might be the choice of therapy of men in the andropause as well. In addition, the pro-drug approach we propose here could provide an impetus for drug discovery of other related or un-related therapies. PUBLIC HEALTH RELEVANCE: Peri-menopausal hot flushes pose a significant public health concern world-wide. Although hormone replacement therapy, alleviates hot flushes in the majority of women, a large number of peri-menopausal women cannot take or do not want to take hormones. Therefore, there is still a huge unmet need for better and safer therapies for menopausal symptoms. The proposal addresses this unmet need by investigating a potentially liability-free estrogen replacement therapy, i.e., the use of para-quinol of estrogen as a prodrug approach. The prodrug is converted to estrogen in brain but not uterus and breast, and as a result, it blunts hot flushes in an animal model of hot flush.